Effect of nitrates on left ventricular size and function during exercise: Comparison of sublingual nitroglycerin and nitroglycerin paste

To compare the effects of sublingual nitroglycerin and nitroglycerin paste on left ventricular size and performance during supine bicycle exercise, equilibrium radionuclide angiography was performed in 36 persons classified into two groups of normal subjects and two groups of patients with angiographically proved coronary heart disease. Each group underwent a control exercise study, and then one group of normal subjects and one group of patients were restudied after the administration of 0.6 mg of nitroglycerin or 2 inches (5 cm) of nitroglycerin paste (but not both). Data were collected at rest and at peak exercise.In normal subjects exercise resulted in increased ejection fraction, decreased end-systolic volume and little change in end-diastolic volume. After either drug, volumes at rest markedly decreased, and during exercise, ejection fraction increased to levels comparable with pre-drug levels. After nitroglycerin paste the reduction in volume seen at rest persisted during exercise, but after sublingual nitroglycerin end-diastolic volume increased during exercise (88 ± 43 to 113 ± 30 ml [mean ± standard deviation]; p < 0.01). Peak exercise end-diastolic volume after nitroglycerin was still lower than that before nitroglycerin (113 ± 30 versus 120 ± 28 ml, p < 0.05).In patients with coronary disease, ejection fraction did not change during exercise, but both end-diastolic and end-systolic volumes increased. After either drug ejection fraction at rest was unchanged, although ventricular volumes were markedly lower (p < 0.05). Ejection fraction increased with exercise in both groups with coronary disease after either drug. After sublingual nitroglycerin, volumes increased during exercise although the peak exercise end-diastolic volume was still lower than the control value (113 ± 31 versus 145 ± 34 ml; p < 0.01). After paste administration, end-diastolic volume did not change during exercise, and end-systolic volume decreased (41 ± 20 to 36 ± 22 ml; p < 0.05).Thus, sublingual nitroglycerin and nitroglycerin paste improved left ventricular function during exercise. The effect of paste on end-diastolic volume appeared sustained, whereas that of sublingual nitroglycerin was transient, confirming the hypothesis that reduction in end-diastolic volume and, by implication, left ventricular wall tension, is a major mechanism of nitrate action.     

Ineffectiveness of sublingual nitroglycerin in acute left ventricular failure in the presence of massive peripheral edema

Although it has been postulated that peripheral edema may reduce venous compliance in patients with congestive heart failure, this possibility has not yet been Investigated. Sublingual nitroglycerin, 1.6 to 2.4 mg, was administered to 15 patients with acute left ventricular failure, including 8 patients without peripheral edema (group I) and 7 patients with massive peripheral edema (group II). Baseline hemodynamic variables were similar in the two groups. In group I, sublingual nitroglycerin decreased the left ventricular filling pressure from 28 ± 2 (mean ± 1 standard deviation) to 14 ± 3 mm Hg (p < 0.005), whereas cardiac output increased from 3.3 ± 0.4 to 4.3 ± 0.3 liters/min (p < 0.005) because of an increase in stroke volume. Right atrial pressure decreased from 28 ± 3 to 13 ± 3 mm Hg (p < 0.005). In group II, no significant hemodynamic changes were induced by nitroglycerin despite the elevated baseline left ventricular filling pressure of 30 ± 5 mm Hg and right atrial pressure of 29 ± 4 mm Hg. Five patients from group II were rechallenged with sublingual nitroglycerin 18 days after furosemide therapy, when the peripheral edema had cleared (6 kg weight loss). At this time there were significant decreases in left ventricular filling pressure (from 13 ± 2 to 9 ± 2 mm Hg; p < 0.025) and right atrial pressure (from 13 ± 1 to 9 ± 2 mm Hg; p < 0.005); cardiac output was not increased, probably because of the normal baseline left ventricular filling pressure. These results indicate that through various mechanisms massive peripheral edema decreases venous compliance and therefore prevents nitroglycerin from reducing preload.     

Alteration of Left Ventricular Diastolic Function During Coronary Angioplasty-Induced Ischemia: A Color M-Mode Doppler Study

Objectives. The aim of this study was to assess the effects of ischemia on diastolic function by analyzing flow propagation velocity with color M-mode Doppler echocardiography.Background. Color M-mode Doppler echocardiography has been proposed as a method of assessing left ventricular filling.Methods. Color M-mode Doppler echocardiography and measurement of hemodynamic data were performed simultaneously at baseline and during angioplasty-induced ischemia. Tau was compared with flow propagation velocity. Late diastolic indexes, left ventricular pressure and flow cessation time were also investigated.Results. During ischemia, left ventricular relaxation rate (tau) increased, whereas flow propagation velocity decreased, from (mean ± SD) 46.8 ± 10 ms to 72.6 ± 18.3 ms and from 59.8 ± 15.8 cm/s to 30 ± 8 cm/s, respectively (all p < 0.0001). The maximal slowing of flow propagation velocity was observed 20 to 30 s after the beginning of the inflation, coexisting with a notch on the ascending limb of the negative rate of rise of the left ventricular pressure (dP/dt) curve. Flow propagation velocity was correlated with tau both at baseline (r = 0.53, p < 0.05) and during inflation (r = 0.53, p < 0.03). Left ventricular end-diastolic pressure increased during ischemia from 13.5 ± 8 mm Hg at baseline to 27.5 ± 7 mm Hg, while a premature cessation of the entering flow occurred −13.8 ± 23 ms before the next Q wave onset, compared with 4.5 ± 19.6 ms after the Q wave onset at baseline (all p < 0.0001).Conclusions. The analysis of flow propagation velocity showed that early filling is highly dependent on left ventricular relaxation rate, particularly through the phenomenon of asynchrony. During ischemia, the premature cessation of late filling is associated with increased diastolic pressures.(J Am Coll Cardiol 1997;29:1246–55)     

Hemodynamic and electrophysiologic effects of verapamil and nifedipine in patients on propranolol

Because the combined use of a beta-adrenergic blocking agent and a calcium antagonist may be beneficial in patients with severe angina, we assessed the hemodynamic and electrophysiologic effects of verapamil or nifedipine in patients receiving oral propranolol. In 26 patients with stable angina receiving oral propranolol (234 ± 230 mg/day, mean ± standard deviation), cardiac catheterization was performed, and variables were measured at baseline and 5 to 10 minutes after (1) intravenous saline solution, 10 ml (n = 6); (2) intravenous verapamil, 0.15 mg/kg body weight to a maximal dose of 10 mg (n = 10); and (3) sublingual nifedipine, 10 mg (n = 10). Cardiac output (by thermodilution) was unchanged after saline solution and verapamil but increased with nifedipine (4.3 ± 1.1 to 5.0 ± 1.4 liters/min, p < 0.05). Mean arterial pressure did not change with saline solution or nifedipine but decreased with verapamil. Peak-positive dP/dt was reduced only by verapamil (from 1,086 ± 175 to 926 ± 167 mm Hg/s, p < 0.05). Coronary sinus blood flow (by thermodilution) was not altered by saline solution, nifedipine, or verapamil. Verapamil reduced the heart rate (from 63 ± 8 to 60 ± 9 beats/min, p < 0.05) and increased the A-H interval (from 108 ± 14 to 129 ± 23 ms, p < 0.05). In contrast, nifedipine increased the heart rate (from 65 ± 8 to 71 ± 8 beats/min, p < 0.05) but did not change the A-H interval. Left ventricular ejection fraction (by radionuclide ventriculography) was unaltered by saline solution or verapamil but increased with nifedipine (from 0.52 ± 0.13 to 0.57 ± 0.13, p < 0.05). In summary, when administered to patients with normal or only mildly depressed left ventricular function who are receiving oral propranolol, nifedipine improves cardiac output and left ventricular ejection fraction without affecting intracardiac filling pressure or atrioventricular conduction. In contrast, verapamil diminishes left ventricular contractility and slows atrioventricular conduction. Thus, the combination of verapamil and propranolol must be used with caution in patients with underlying left ventricular dysfunction or conduction system disease.     

Intracavitary filling pattern in the failing left ventricle assessed by color M-mode Doppler echocardiography

Objectives. The present study aimed to investigate the mechanism of intracavitary changes in filling pattern during acute ischemic left ventricular failure and during beta-adrenergic blockade.Background. Recent clinical studies with color M-mode Doppler imaging have shown abnormal intracavitary filling patterns in the diseased ventricle.Methods. In open chest anesthetized dogs with intracardiac micromanometers and myocardial segment-length crystals, global ischemic left ventricular failure was induced (n = 8) by coronary microembolization. In nonischemic ventricles inotropy was decreased (n = 6) by intravenous propranolol and increased (n = 6) by intravenous isoproterenol. From color M-mode Doppler images we calculated the time difference between peak early diastolic filling velocity at the mitral tip and apex using computer analysis. The time difference of peak velocity was used as an index of the timing of apical filling.Results. There was marked retardation of apical filling with microembolization and propranolol. Time difference of peak velocity increased from 20 ± 6 (mean ± SEM) to 101 ± 17 ms (p < 0.05) and from 21 ± 8 to 80 ± 18 ms (p < 0.05), respectively. Time constant of isovolumic relaxation increased from 34 ± 3 to 43 ± 5 ms (p < 0.05) and from 31 ± 1 to 39 ± 3 ms (p < 0.05) during microembolization and beta-blockade, respectively. Isoproterenol tended to cause the opposite changes. Time difference of peak velocity showed a positive correlation with time constant of isovolumic relaxation (r = 0.89, p < 0.01) and a negative correlation with peak early transmitral pressure gradient (r = 0.88, p < 0.01 ). In the intact left ventricle, peak apical filling velocity coincided with peak early transmitral pressure gradient. During ischemic failure, however, peak apical filling velocity occurred 53 ± 14 ms after peak early transmitral pressure gradient had decreased to zero and at a time when transmitral flow had ceased, suggesting a change in intraventricular flow distribution.Conclusions. Color M-mode Doppler imaging revealed retarded apical filling during depression of myocardial function by global myocardiai ischemia or beta-blockade. The abnormal filling pattern may be a sign of impaired left ventricular relaxation.     

Transdermal nitroglycerin patch therapy reduces the extent of exercise-induced myocardial ischemia: Results of a double-blind,placebo-controlled trial using quantitative thallium-201 tomography

Objectives. This study prospectively evaluated whether transdermal nitroglycerin patches could limit the extent of exercise-induced left ventricular ischemia as assessed by quantitative thallium-201 tomography.Background. Although antianginal medications are effective at reducing chest pain symptoms in patients with coronary artery disease, there is limited evidence that these agents can also reduce myocardial ischemia.Methods. This was a randomized, double-blind, parallel, placebo-controlled trial evaluating nitroglycerin patch therapy in patients in stable condition with angiographic coronary artery disease and no previous myocardial infarction. All patients were weaned from antianginal agents and had a baseline symptom-limited treadmill test followed by thallium-201 tomography. Forty patients with perfusion defects involving ≥5% of the left ventricle were randomized to receive either intermittent (12 h on/off) active nitroglycerin patch therapy (0.4 mg/h) or placebo. Exercise tomography was repeated a mean (±SD) of 6.1 ± 1.8 days after randomization.Results. Patients randomized to receive active patch therapy had a significant reduction in their total perfusion defect size (−8.9 ± 11.1%) compared with placebo-treated patients (−1.8 ± 6.1%, p = 0.04), which was most apparent in those with the largest (≥20%) baseline perfusion defects (−11.4 ± 13.4% vs. 1.0 ± 3.6%, respectively, p < 0.02). Furthermore, 7 (33%) of 21 patients receiving active therapy had a ≥10% decrease in their perfusion defects compared with only 1 (5%) of 19 patients randomiztd to receive placebo (p = 0.002). Nitrate therapy did not significantly reduce heart rate, blood pressure or double product, indicating benefit through enhancement of coronary blood flow.Conclusions. Short-term, intermittent nitroglycerin patch therapy significantly reduces myocardial ischemia, particularly in patients with large ischemic perfusion defects. Thallium-201 tomography can be used to assess sequential changes in the extent of exercise-induced left ventricular ischemia.     

Effect of nifedipine on exercise-induced left ventricular dysfunction and myocardial hypoperfusion in stable angina

To assess the effects of nifedipine on left ventricular function and regional myocardial perfusion, exercise radionuclide ventriculography was performed in 15 men (median age 59 years) and exercise thallium-201 scintigraphy was done in 11 of them, before and 90 minutes after the oral administration of 20 mg of nifedipine. All patients had stable angina and angiographically proved coronary artery disease without evidence of spasm. Exercise tolerance after administration of nifedipine increased from 343 ± 42 seconds to 471 ± 50 seconds (p < 0.01), whereas the peak exercise double product remained essentially unchanged (difference not significant). Ejection fraction improved significantly at rest (from 49 ± 3.6% to 52 ± 3.3%, p < 0.05) and at peak exercise (42 ± 3.3% to 47 ± 3.7%, p < 0.05). Nifedipine also resulted in an improved segmental wall motion score (4.3 ± 2.3 to 3.0 ± 2.3, p < 0.05; 0 = normal and 4 = worst degree of dysfunction). The ejection fraction increased by more than 5% in one third of the patients at rest, and in more than half of the patients at peak exercise. Improved exercise myocardial perfusion occurred in 5 of 11 patients (45%) and in 7 of 28 segments (25%) with reversible hypoperfusion. Thus, nifedipine produces significant improvement in global and regional left ventricular function in patients with coronary artery disease and stable angina. This may be accounted for, at least in part, by improvement in myocardial perfusion.     

Influence of left ventricular hypertrophy on left ventricular function during dynamic exercise in the presence or absence of coronary artery disease

Objectives. We investigated the influence of left ventricular hypertrophy in the presence or absence of coronary artery disease on hemodynamic characteristics during exercise in subjects without previous myocardial infarction.Background. Left ventricular hypertrophy has been found to increase the vulnerability of the myocardium to the development of ischemia. However, the independent influences of left ventricular hypertrophy and coronary artery disease have not been assessed in humans.Methods. Symptom-limited supine leg exercise tests were performed by 78 patients. They were classified into the following subgroups: no coronary artery disease or left ventricular hypertrophy (group I, n = 30), left ventricular hypertrophy only (group II, n = 12), coronary artery disease only (group III, n = 20) and both left ventricular hypertrophy and coronary artery disease (group IV, n = 16). Mean left ventricular mass index was 105, 158, 109 and 159 g/m²in groups I to IV, respectively.Results. Pulmonary artery wedge pressure increased from 6 ± 3 (mean ± SD) mm Hg at rest to 10 ± 5 mm Hg at peak exercise in group I, from 8 ± 2 to 18 ± 8 mm Hg in group II (p < 0.05 vs. group I), from 6 ± 3 to 23 ± 6 mm Hg in group III (p < 0.01 vs. group I) and from 8 ± 4 to 30 ± 7 mm Hg in group IV (p < 0.01 vs. group I; p < 0.01 vs. group II; p < 0.05 vs. group III). Multiple regression analysis showed that the number of diseased coronary vessels and left ventricular mass index were independent predictors of peak pulmonary artery wedge pressure (F = 59.2 and 19.1, respectively; multiple correlation coefficient r = 0.74, p < 0.0001).Conclusions. Left ventricular hypertrophy and coronary artery disease independently increased left ventricular filling pressure during supine leg exercise. Severe left ventricular dysfunction was induced by exercise when both conditions were present.     

Effects of nitroglycerin on supine and upright exercise in mitral stenosis

Resting, supine, and upright exercise hemodynamics were studied in 11 patients with pure or predominant mitral stenosis before and after 0.4 mg sublingual nitroglycerin. Resting mean pulmonary wedge pressure was reduced from 27 ± 1.6 to 21 ± 1.6 mm Hg (p < 0.001), while mean cardiac index (2.98 ± 0.40 vs 2.68 ± 0.30 cc/min/m²; NS) and mean heart rate (82 ± 4.4 vs 87 ± 6.7 bpm; NS) were unchanged after nitroglycerin. Resting mean left ventricular end-diastolic pressure dropped from 11 ± 1.7 to 8 ± 1.1 mm Hg (p < 0.02) after nitroglycerin, while stroke index (37 ± 5.1 vs 32 ± 3.8 mm Hg; NS) was unchanged. Left ventricular systolic pressure fell from 122 ± 6.0 to 111 ± 3.1 mm Hg (p < 0.001) after nitroglycerin. At peak supine exercise similar qualitative changes were observed. Mean pulmonary wedge pressure was lower after nitroglycerin (43 ± 2.3 vs 36 ± 2.1 mm Hg; p < 0.02), while cardiac index (3.62 ± 0.39 vs 3.4 ± 0.26 cc/min/m²; NS) and heart rate (116 ± 7.1 vs 113 ± 4.6 bpm; NS) were not different. Left ventricular end-diastolic pressure (13 ± 1.4 vs 10 ± 1.3; NS) was slightly but not significantly reduced by nitroglycerin. Left ventricular stroke index (34 ± 3.4 vs 31 ± 2.2 mm Hg; NS) was unchanged by nitroglycerin. Left ventricular systolic pressure (137 ± 7.3 vs 127 ± 6.1 mm Hg; p < 0.02) was reduced 10 mm Hg at peak supine exercise after nitroglycerin. During upright exercise, peak heart rate (160 ± 8.1 vs 160 ± 8.0 bpm; NS) and peak systolic blood pressure (117 ± 5.7 vs 112 ± 2.8 mm Hg; NS) were not changed with nitroglycerin. Exercise duration was improved after introglycerin (5.02 ± 0.62 vs 5.66 ± 0.65 minutes; p < 0.02). Thus sublingual nitroglycerin lowers mean pulmonary wedge pressure to reduce pulmonary congestive symptoms, improves supine exercise hemodynamics, and may enhance treadmill exercise duration in some patients with pure or predominant mitral stenosis.     

Comparative effects of nitroglycerin, nifedipine and metoprolol on regional left ventricular function in patients with one-vessel coronary disease

To compare acute effects of nitroglycerin (0.8 mg sublingually), nifedipine (5 ng/kg/min i.v.) and metoprolol (0.15 mg/kg i.v.) on normal, ischemic and scarred myocardial segments in man, we performed simultaneous hemodynamic and radionuclide measurements of left ventricular functions. Sixteen patients with isolated left anterior descending (LAD) disease were studied at rest and during exercise. Nine patients had angina and exercise-induced ischemia (LAD stenosis) and seven patients had previous transmural myocardial infarction and no ischemic changes during thallium imaging (LAD occlusion). The effects of the drugs on regional ejection fraction of the involved anteroseptal region and the normal posterolateral area were compared. Global ejection fraction at rest did not change after nitroglycerin, increased after nifedipine and decreased after metoprolol. In patients with ischemia, the exercise ejection fraction improved after all drugs due to increased regional ejection fraction in ischemic segments: i.e., a regional antiischemic effect evidenced by improved regional function could be demonstrated with all three agents. Regional ejection fraction increased from 35.8 +/- 19.5% to 66.2 +/- 15.2% (+/- SD) after nitroglycerin (p less than 0.001), to 61.7 +/- 8.7% after nifedipine (p less than 0.001), and to 48.4 +/- 7.0% after metoprolol (p less than 0.01). In regions of myocardial scar, regional ejection fraction was not changed after any drug. In normal areas, regional ejection fraction remained unchanged after nitroglycerin and nifedipine, but decreased after metoprolol. Despite similar antiischemic effects of all three drugs, underlying hemodynamic mechanisms were quite different and may provide a rationale for combined forms of treatment. These results may help to select optimal drug combinations to improve myocardial performance in patients with chronic ischemic heart disease.     

Verapamil in stable effort angina: Effects on left ventricular function evaluated with exercise radionuclide ventriculography

A double blind placebo-controlled study was performed in 12 patients with stable angina pectoris to evaluate the effects of oral verapamil (320 mg/day) on left ventricular function, as measured at rest and during exercise with gated equilibrium radionuclide ventriculography. On verapamil, patients had a lower heart rate-blood pressure product at each work load than with placebo. Anginal threshold increased by 28 ± 19 watts (p < 3.005), and maximal exercise capacity increased by 20 ± 14 watts (p < 0.001) with verapamil, but the rate-pressure product at the onset of angina and at maximal exercise was unchanged. Left ventricular ejection fraction at rest during verapamil therapy was the same as with placebo therapy. On exercise during placebo therapy, the ejection fraction decreased from 40 ± 9 to 35 ± 11 percent (p < 0.025) because end-systolic volume increased disproportionately compared with end-diastolic volume. On exercise during verapamil therapy, the ejection fraction did not decrease (44 ± 8 versus 45 ± 12 percent) and was significantly higher at identical work loads than on placebo because of a smaller increase in end-systolic volume. Oral verapamil is effective treatment for effort angina and may prevent the decrease in left ventricular ejection fraction due to exercise-induced ischemia.     

Comparison of hemodynamic responses to nifedipine and nitroprusside in severe chronic congestive heart failure

The hemodynamic effects of 20 to 40 mg of oral nifedipine were compared with those of intravenous nitroprusside in 11 patients with severe chronic congestive heart failure (CHF). In each patient, both drugs were administered to produce similar reduction of systemic vascular resistance (SVR) (29 ± 13% with nifedipine and 29 ± 12% with nitroprusside, difference not significant [NS]). At this comparable decrease in systemic vascular resistance, significant differences in hemodynamic responses to both drugs were noted: Nifedipine caused a smaller increase in cardiac index (20 ± 20% vs 40 ± 24%, p < 0.02) and a larger decrease in mean blood pressure than nitroprusside (16 ± 9% vs 8 ± 10%, p < 0.05). In addition, nifedipine produced a smaller decrease in mean pulmonary artery wedge pressure (13 ± 24% vs 36 ± 21%, p < 0.001) and pulmonary vascular resistance than nitroprusside (6 ± 42% vs 26 ± 46%, NS. Mean right atrial pressure decreased with nitroprusside, from 10 ± 7 to 5 ± 3 mm Hg (p < 0.05), but not with nifedipine (10 ± 7 mm Hg before and after nifedipine administration, NS). Left ventricular stroke work index increased with nitroprusside (20 ± 8 to 27 ± 9 g-m/m², p < 0.05), but did not change with nifedipine (21 ± 9 vs 21 ± 10 g-m/m², NS). These data show that nifedipine has an arteriolar dilatatory action in patients with CHF. However, compared with nitroprusside, nifedipine had a significantly larger hypotensive effect and had a lesser effect on right and left ventricular filling pressure, cardiac output and left ventricular function.     

The significance of nitroglycerin-induced changes in ventricular function after acute myocardial infarction

The potential of nitroglycerin for improving global and regional ventricular function after acute myocardial infarction and predicting serial change in ventricular function at the time of hospital discharge was investigated. Equilibrium multiple gated blood pool scintigrams were performed at rest before and after sublingual administration of nitroglycerin in 18 patients an average of 36 hours after infarction and again at discharge. Global right and left ventricular function and regional left ventricular function of infarct and noninfarct zones were determined scintigraphically.In the early study nitroglycerin increased both mean (± standard deviation) left ventricular ejection fraction (0.51 ± 0.15 to 0.55 ± 0.15; p < 0.02) and mean right ventricular ejection fraction (0.42 ± 0.14 to 0.47 ± 0.13; p < 0.05). Left ventricular ejection fraction significantly increased in 5 of the 18 patients. It Increased late in five of the six patients who exhibited an increase early after nitroglycerin but in only 2 of the 12 patients who did not exhibit an early increase (p < 0.06). Regional ejection fraction in the infarct zone increased late in 7 of the 12 patients who exhibited an early increase after nitroglycerin and in none of the 6 who did not exhibit an early increase (p < 0.05). Both right and left ventricular global ejection fraction and regional ejection fraction showed little late responsiveness to nitroglycerin.Early after infarction, sublingual nitroglycerin improved left, right and regional ejection fraction at the infarct site in some patients. These nitroglycerin-induced changes predicted those patients whose global ventricular function and regional left ventricular function at the infarct site improved late.     

Effects of nitroglycerin on isometric exercise

Eight patients with ischemic heart disease performed isometric handgrip of five minutes' duration at 30% of their maximum voluntary contraction, before and after administration of 0.4 mg sublingual nitroglycerin (NTG). Although isometric exercise resulted in similar rise of left ventricular systolic pressure (LVSP) before and after NTG, the level of LVSP during the post NTG effort was lower. Heart rate, cardiac index, stroke index, left ventricular stroke work index, and systemic resistance were not different during the pre- and post NTG exercise. Left ventricular end-diastolic pressure rose to a significantly lower level (18.3 ± 14.4 mm Hg) during the post NTG handgrip than during the pre NTG effort (31.4 ± 17.6 mm Hg, P < 0.005). It is concluded that NTG reduces preload and afterload both at rest and during isometric exercise and improves left ventricular performance during isometric exercise.     

External,noninvasive cardiac assistance and nitrate administration for patients with unstable angina pectoris or acute coronary insufficiency

The influence of external, noninvasive counterpulsation, alone and in combination with sublingual nitroglycerin or isosorbide dinitrate, on left ventricular volumes and ejection fractions was investigated. Patients with unstable angina pectoris or acute coronary insufficiency were selected for this evaluation. Left ventricular volumes and ejection fractions were estimated using a gated blood pool scintigraphic technique. Twenty minutes of external counterpulsation did not significantly alter left ventricular end-diastolic volumes, end-systolic volumes, or ejection fractions in 13 patients. When sublingual isosorbide dinitrate (10 mg.) was combined with 20 minutes of external counterpulsation in eight patients, left ventricular end-diastolic volumes decreased 16 ± 7 per cent (p = .05), but neither left ventricular end-systolic volumes (12 ± 7 per cent) nor ejection fractions were significantly changed. When sublingual nitroglycerin (0.4 mg.) was combined with 15 minutes of external counterpulsation in three patients, left ventricular end-diastolic volumes decreased 21 ± 3 per cent (p < .01), end-systolic volumes decreased 25 ± 4 per cent (p < .02), and ejection fractions were not significantly changed. When left ventricular volumes and ejection fractions were measured 30 and 65 minutes after isosorbide dinitrate administration, 10 and 45 minutes after cessation of external counterpulsation, respectively, left ventricular end-diastolic volumes and end-systolic volumes were significantly decreased by approximately 20 per cent while ejection fractions were unchanged. When left ventricular volumes and ejection fractions were measured 25 minutes after nitroglycerin administration, 10 minutes after cessation of external counterpulsation, end-systolic volumes decreased 23 ± 2 per cent (p < .005) and end-diastolic volumes decreased 27 ± 3 per cent (p < .005). No significant changes in left ventricular end-diastolic or end-systolic volumes were seen 60 minutes after nitroglycerin administration. As in the other studies, left ventricular ejection fractions were unchanged. The results suggest that relatively short periods of external, noninvasive cardiac assistance do not alter left ventricular volumes or ejection fractions in patients with unstable angina pectoris or acute coronary insufficiency. Although external counterpulsation combined with a vasodilator such as isosorbide dinitrate or nitroglycerin decreases left ventricular volumes, it offers no advantage over vasodilator treatment alone.     

Addition of zatebradine,a direct sinus node inhibitor,provides no greater exercise tolerance benefit in patients with angina taking extended-release nifedipine: results of a multicenter,randomized, double-blind,placebo-controlled,parallel-group study

Objectives. We examined the antianginal and anti-ischemic effects of oral zatebradine, a direct sinus node inhibitor that has no blood pressure-lowering or negative inotropic effects in patients with chronic stable angina pectoris taking extended-release nifedipine.Background. Heart rate reduction is considered an important pharmacologic mechanism for providing anginal pain relief and anti-ischemic action in patients with chronic stable angina, suggesting a benefit for sinus node-inhibiting drugs.Methods. In a single-blind placebo run-in, randomized double-blind, placebo-controlled, multicenter study, patients already receiving extended-release nifedipine (30 to 90 mg once a day) were randomized to receive zatebradine (5 mg twice a day [n = 64]) or placebo (n = 60). All subjects had reproducible treadmill exercise-induced angina at baseline, and after randomization they performed a serial exercise test 3 h after each dose for 4 weeks.Results. Zatebradine reduced rest heart rate both at 4 weeks ([mean ± SEM] 12.9 ± 1.23 vs. 2.3 ± 1.6 [placebo] beats/min, p < 0.0001) and at the end of comparable stages of Bruce exercise (16.7 ± 1.2 vs. 3.4 ± 1.2 [placebo] beats/min, p < 0.0001). Despite the significant effects on heart rate at rest and exercise, there were no additional benefits of zatebradine from placebo baseline in measurements of total exercise duration, time to 1-mm ST segment depression or time to onset of angina. Subjects taking zatebradine also had more visual disturbances as adverse reactions.Conclusions. Zatebradine seems to provide no additional anti-anginal benefit to patients already receiving nifedipine, and it raises questions regarding the benefit of heart rate reduction alone as an antianginal approach to patients with chronic stable angina.     

Increased Atrial Contribution to Left Ventricular Filling Compensates for Impaired Early Filling During Exercise in Heart Failure With Preserved Ejection Fraction

BackgroundThe role of left atrial (LA) function on exercise remains poorly understood in heart failure with preserved ejection fraction (HfpEF) despite its key role in optimizing left ventricular (LV) diastolic function. We used resting and exercise radionuclide ventriculography to investigate the role of LA function in the pathophysiology of HfpEF.Methods and ResultsA total of 25 patients with HfpEF and 15 age- and gender-matched controls were recruited. All subjects underwent resting echocardiogram, metabolic exercise testing to peak effort, and radionuclide ventriculography (at rest and exercise [to 35% of heart rate reserve]). At rest LA and LV function were similar in patients and controls. During exercise, HfpEF patients had lower left ventricular ejection fraction (69 ± 9% vs. 73 ± 10%, P < .05) and lower peak early filling rate (387 ± 109 end-diastolic count/sec vs. 561 ± 156 end-diastolic count/sec, P < .001). During exercise, the atrial contribution to LV filling was significantly higher in patients than controls (46 ± 11% vs. 30 ± 9%, P < .001). Atrial contribution to LV filling correlated negatively with peak early filling rate during exercise (r = -0.6, P < .001). Peak early filling rate correlated positively with peak oxygen consumption (r = 0.485, P = .004) and negatively with minute/carbon dioxide production (r = -0.423, P = .013).ConclusionPatients with HfpEF have increased atrial contribution to LV filling as a compensatory response to impaired early LV filling during cycle exercise.     

Effects of digoxin on left ventricular function in coronary artery disease patients

To assess whether digitalis modifies or prevents the deterioration of the left ventricular ejection fraction and wall motion during acute ischemia, we performed gated blood pool radionuclide ventriculograms in 15 patients with angiographically documented coronary artery disease. All patients were studied in the resting state and during maximal supine bicycle exercise, both before and 1 hour after 1 mg intravenous digoxin.There was no significant difference, pre-digoxin vs post-digoxin, in exercise tolerance (415 ± 84 vs 418 ± 107 seconds), number of segments with abnormal resting wall motion (12 vs 11) or exercise wall motion (21 vs 19). Ten patients developed angina during the same exercise load, irrespective of digoxin administration. Twelve patients had subnormal left ventricular ejection fraction during exercise pre-digoxin, vs 13 patients post-digoxin (P = ns). In the resting state, the left ventricular ejection fraction was higher after digoxin (53 ± 14% pre vs 58 ± 14% post, P < 0.05). During exercise, however, the left ventricular ejection fraction was not significantly improved after digoxin (50 ± 16% pre vs 53 ± 17% post, P = ns).These data indicate that although acute administration of digoxin improves the resting left ventricular function, it does not improve exercise tolerance to angina. Furthermore, intravenous digoxin does not appear to prevent the deterioration of left ventricular wall motion and ejection fraction during exercise induced ischemia.     

Left ventricular response to isometric exercise and its value in predicting the change in ventricular function after mitral valve replacement for mitral regurgitation

Reduced left ventricular (LV) afterload and its effect on the resting ejection fraction may lead to over-estimation of LV function in mitral regurgitation (MR). To evaluate LV function during increased afterload of the heart, an isometric handgrip test was performed during cardiac catheterization in 15 patients with mitral regurgitation (MR group) and in 9 normal subjects (normal group). Twelve months after successful mitral valve replacement (MVR) the patients were recatheterized, and the value of preoperative stress testing in predicting the change in resting ventricular function after surgery was estimated.Isometric exercise caused an increase in end-systolic wall stress, a measure of ventricular afterload, in both the MR group and the control group (p < 0.001). The ejection fraction remained unchanged in the control group, but decreased from 0.58 ± 0.08 to 0.53 ± 0.08 in the MR group (p < 0.001). After MVR, end-systolic wall stress increased significantly (p < 0.001) and the ejection fraction decreased from 0.58 ± 0.05 to 0.51 ± 0.1 (p < 0.05). A positive correlation existed between the change in the ejection fraction during preoperative stress testing and the change in the resting ejection fraction after MVR (r = 0.65, p < 0.01). In 8 patients whose resting ejection fraction was within normal limits (> 0.55) preoperatively, the ejection fraction was depressed (< 0.55) 1 year after surgery. In all but 1 of these patients the isometric exercise revealed the reduced ventricular response to afterload stress preoperatively (decrease of the ejection fraction > 0.03 during exercise). Therefore, the isometric exercise-induced change in LV function appears to predict the influence of MVR on LV function.     

Myocardial dysfunction after resuscitation from cardiac arrest: An example of global myocardial stunning

Objectives. This study investigated the effect of prolonged cardiac arrest and subsequent cardiopulmonary resuscitation on left ventricular systolic and diastolic function.Background. Cardiac arrest from ventricular fibrillation results in cessation of forward blood flow, including myocardial blood flow. During cardiopulmonary resuscitation, myocardial blood flow remains suboptimal. Once the heart is defibrillated and successful resuscitation achieved, reversible myocardial dysfunction, or “stunning,” may occur. The magnitude and time course of myocardial stunning from cardiac arrest is unknown.Methods. Twenty-eight domestic swine (26 ± 1 kg) were studied with both invasive and noninvasive measurements of ventricular function before and after 10 or 15 min of untreated cardiac arrest. Contrast left ventriculograms, ventricular pressures, cardiac output, isovolumetric relaxation time (tau) and transthoracic Doppler-echocardiographic studies were obtained.Results. Twenty-three of 28 animals were successfully resuscitated and postresuscitation data obtained. Left ventricular ejection fraction showed a significant reduction 30 min after resuscitation (p < 0.05). Regional wall motion analysis revealed diffuse, global left ventricular systolic dysfunction. Left ventricular end-diastolic pressure increased significantly in the postresuscitation period (p < 0.05). Isovolumetric relaxation time (tau) was significantly increased over baseline by 2 h after resuscitation (p < 0.05). Similar findings were noted with the Doppler-echocardiographic analysis, including a reduction in fractional shortening (p <0.05), a reduction in mitral valve deceleration time (p < 0.05) and an increase in left ventricular isovolumetric relaxation time in 5 h after resuscitation (p < 0.05). By 24 h, these invasive and noninvasive variables of systolic and diastolic left ventricular function had begun to improve. At 48 h, all measures of left ventricular function had returned to baseline levels.Conclusions. Myocardial systolic and diastolic dysfunction is severe after 10 to 15 min of untreated cardiac arrest and successful resuscitation. Full recovery of this postresuscitation myocardial stunning is seen by 48 h in this experimental model of ventricular fibrillation cardiac arrest.